The ras genes encode low molecular weight guanine nucleotide binding proteins that act as a "molecular switches" involved in signaling pathways resulting in cell proliferation. Normal Ras is deactivated by GTP hydrolysis, a reaction catalyzed by the well-characterized GAP proteins. Ras is activated by GDP/GTP exchange, catalyzed by a class of proteins known as exchange factors which have only recently been identified. Details of their activation and regulation are not understood. The proto-oncogene vav encodes a lymphocyte-specific exchange factor for Ras. Our previous experiments show that Vav is regulated by tyrosine phosphorylation. Tyrosine phosphorylated Vav appears within 30 secs of receptor stimulation, accelerating the exchange activity about 10-fold and declining within 3 mins of stimulation. In contrast, Ras activation begins after the peak of Vav activation and is maintained for much longer periods. These different kinetics suggest two possibilities: either Vav activation is unrelated to Ras activation or Vav initiates Ras activation and Ras maintained by another exchange factor. Experiments proposed here, using B cells stimulated through surface immunoglobulin (sIg), are designed to distinguish between these two possibilities. First, the relationship between Vav and Ras will be addressed by over-expression of normal, oncogenic or inactive Vav and the consequences regarding Ras activation will be assessed. Second, the role of Sos, a ubiquitously expressed mammalian exchange factor, in initiation or maintenance of Ras activation, will be studied. Lastly, preliminary data indicate reduced activation of Vav and Ras when sIg and the Fc-gamma receptor are co-crosslinked. This condition has long been known to prevent B cell proliferation; furthermore, it has been proposed to represent a "feedback suppressive" mechanism to prevent excessive Ig secretion. Experiments are proposed to study the mechanism by which Vav and Ras activation are prevented under these conditions. The central regulatory role of Ras proteins in normal cell growth, their oncogenic potential, the prevalence of ras mutations in some 30% of human tumors, the oncogenic potential of the vav gene product, and its identification as a hematopoietic cell-specific, tyrosine kinase-regulated exchange factor, provide a rationale for studies addressing the function and regulation of Vav in the hematopoietic system. If Vav is the physiological activator of Ras, perturbations that release it from normal regulatory mechanisms and, thus, elevate its enzymatic activity, could contribute to constitutive Ras activation and, potentially, to malignant transformation. Alternatively, conditions preventing Vav activation could block transmission of negative signals in the elimination of autoreactive cells, thereby contributing to autoimmune pathology.